KMT2D regulates activation, localization, and integrin expression by T-cells.

Individuals with Kabuki syndrome present with immunodeficiency; however, how pathogenic variants in the gene encoding the histone-modifying enzyme lysine methyltransferase 2D (KMT2D) lead to immune alterations remain poorly understood. Following up on our prior report of KMT2D-altered integrin expression in B-cells, we performed targeted analyses of KMT2D's influence on integrin expression in T-cells throughout development (thymocytes through peripheral T-cells) in murine cells with constitutive- and conditional-targeted Kmt2d deletion. Using high-throughput RNA-sequencing and flow cytometry, we reveal decreased expression (both at the transcriptional and translational levels) of a cluster of leukocyte-specific integrins, which perturb aspects of T-cell activation, maturation, adhesion/localization, and effector function. H3K4me3 ChIP-PCR suggests that these evolutionary similar integrins are under direct control of KMT2D. KMT2D loss also alters multiple downstream programming/signaling pathways, including integrin-based localization, which can influence T-cell populations. We further demonstrated that KMT2D deficiency is associated with the accumulation of murine CD8+ single-positive (SP) thymocytes and shifts in both human and murine peripheral T-cell populations, including the reduction of the CD4+ recent thymic emigrant (RTE) population. Together, these data show that the targeted loss of Kmt2d in the T-cell lineage recapitulates several distinct features of Kabuki syndrome-associated immune deficiency and implicates epigenetic mechanisms in the regulation of integrin signaling.

Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study.

Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.

Autoimmune Vestibulocerebellar Syndromes.

Autoimmune disorders affecting the vestibular end organs, vestibular pathways, vestibular nuclei, and vestibulocerebellum are often underrecognized as a cause of chronic dizziness and ataxia. Autoantibodies specific for cell-surface, synaptic, and intracellular neural antigens serve as biomarkers of these disorders. This article describes the epidemiology, clinical presentation, diagnostic considerations, imaging findings, treatment, and prognosis of autoimmune disorders, in which the vestibulocerebellar syndrome is the main or presenting clinical presentation. Antibodies specific for intracellular antigenic targets described in the article are PCA-1 (Purkinje cell cytoplasmic antibody type 1, also known as anti-Yo), ANNA-1 (antinuclear neuronal antibody type 1, also known as anti-Hu), ANNA-2 (antinuclear neuronal antibody type 2, also known as anti-Ri), Ma1/2 (anti-Kelch-like 11/12 antibody), Kelch-like 11, amphiphysin, CV2 (collapsin response 2, also known as collapsin response mediator protein-5 [CRMP5]), VGCC (voltage-gated calcium channel), GAD65 (glutamic acid decarboxylase 65-kDa isoform), AP3B2 (adaptor protein 3B2, also known as anti-Nb), MAP1B (microtubule-associated protein 1B antibody, also known as anti-PCA-2), and neurochondrin antibodies. Antibodies targeting cell-surface or synaptic antigenic targets described in the article include DNER (delta/notchlike epidermal growth factor related receptor; antigen to anti-Tr), CASPR2 (contactin-associated proteinlike 2), septin-5, Homer-3, and mGluR1 (metabotropic glutamate receptor 1). The vestibulocerebellar presentation is largely indistinguishable among these conditions and is characterized by subacute onset of cerebellar symptoms over weeks to months. The diagnosis of autoimmune vestibulocerebellar syndromes is based on a combination of clinical and serological features, with a limited role for neuroimaging. Subtle eye movement abnormalities can be an early feature in many of these disorders, and therefore a meticulous vestibulo-ocular examination is essential for early and correct identification. Cancer occurrence and its type are variable and depend on the autoantibody detected and other cancer risk factors. Treatment comprises immunotherapy and cancer-directed therapy. Acute immunotherapies such as intravenous immunoglobulin, plasma exchange, and steroids are used in the initial phase, and the use of long-term immunosuppression such as rituximab may be necessary in relapsing cases. Outcomes are better if immunotherapy is started early. The neurologic prognosis depends on multiple factors.

Immunopathological manifestations in Kabuki syndrome: a registry study of 177 individuals.

PURPOSE: Kabuki syndrome (KS) (OMIM 147920 and 300867) is a rare genetic disorder characterized by specific facial features, intellectual disability, and various malformations. Immunopathological manifestations seem prevalent and increase the morbimortality. To assess the frequency and severity of the manifestations, we measured the prevalence of immunopathological manifestations as well as genotype-phenotype correlations in KS individuals from a registry. METHODS: Data were for 177 KS individuals with KDM6A or KMT2D pathogenic variants. Questionnaires to clinicians were used to assess the presence of immunodeficiency and autoimmune diseases both on a clinical and biological basis. RESULTS: Overall, 44.1% (78/177) and 58.2% (46/79) of KS individuals exhibited infection susceptibility and hypogammaglobulinemia, respectively; 13.6% (24/177) had autoimmune disease (AID; 25.6% [11/43] in adults), 5.6% (10/177) with ≥2 AID manifestations. The most frequent AID manifestations were immune thrombocytopenic purpura (7.3% [13/177]) and autoimmune hemolytic anemia (4.0% [7/177]). Among nonhematological manifestations, vitiligo was frequent. Immune thrombocytopenic purpura was frequent with missense versus other types of variants (p = 0.027). CONCLUSION: The high prevalence of immunopathological manifestations in KS demonstrates the importance of systematic screening and efficient preventive management of these treatable and sometimes life-threatening conditions.

Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. OBJECTIVE: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). METHODS: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/ßGeo) mouse model and validated select findings in a patient with KS. RESULTS: Compared with wild-type littermates, Kmt2d+/ßGeo mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d+/ßGeo mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d+/ßGeo mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. CONCLUSIONS: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.

Diabetes in the practice of otolaryngology.

Diabetes mellitus is the most common endocrine disease, characterized by chronic hyperglycemia. The hyperglycemic milieu leads to endothelial injury in blood vessels of variant size, which results in microangiopathy and macroangiopathy (atherosclerosis). Consequential ischemia of nerves and hyperglycemia by itself lead to nerve degeneration and generalized neuropathy, affecting most often the sensory peripheral nerves and the autonomic nervous system. Auditory, vestibular and olfactory sensorium may be compromised by DM. People with DM have an increased susceptibility to infection, as a result of neutrophil dysfunction and impaired humoral immunity. Therefore DM predisposes to certain infectious diseases, such as fungal sinusitis or malignant otitis externa, which are rare in general population. Recovery from infections or from injuries may be compromised by coexisting DM. In this review we discuss complications of DM in the head and neck region. Otolaryngologists and general practitioners should be alert to specific conditions related to DM and be minded of the relevant complications and consequences.

Sirolimus as an alternative treatment in patients with granulomatous-lymphocytic lung disease and humoral immunodeficiency with impaired regulatory T cells.

BACKGROUND: One of the most frequent non-infectious complications of humoral immunodeficiencies with a CVID-like pattern is a particular form of inflammatory lung disease which is called granulomatous-lymphocytic interstitial lung disease (GLILD). Its development worsens patient prognosis, with a significant decrease in survival. Currently, there are no unified guidelines regarding its management, and different combinations of immunosuppressants have been used with variable success. METHODS: Clinical and radiological data were collected from patient's medical charts. Flow cytometry was performed to characterize the immunological features with special focus in regulatory T cells (Tregs). RESULTS: A 16-year-old girl with Kabuki syndrome and a 12-year-old boy, both with a CVID-like humoral immunodeficiency on immunoglobulin replacement treatment, developed during follow-up an inflammatory complication radiologically, clinically, and histologically compatible with GLILD. They required treatment, and sirolimus was started, with very good response and no serious side effects. CONCLUSIONS: These 2 cases provide insight into the underlying local and systemic immune anomalies involved in the development of GLILD, including the possible role of Tregs. Combined chemotherapy is commonly used as treatment for GLILD when steroids fail, but there have been some reports of successful monotherapy. As far as we know, these are the first 2 GLILD patients treated successfully with sirolimus, suggesting the advisability of further study of mTOR inhibitors as a more targeted treatment for GLILD, if impairment in Tregs is demonstrated.

Humoral deficiency in three paediatric patients with genetic diseases.

BACKGROUND: Primary immunodeficiencies (PID) represent a heterogeneous group of genetic disorders characterised by poor or absent function in one or more components of the immune system. Humoral or antibody immunodeficiencies are the most common form of PID, of which common variable immunodeficiency (CVID) is the most frequent symptomatic form. CVID is usually characterised by hypogammaglobulinaemia with poor antibody specificity, and an increased susceptibility to infections, autoimmunity and lymphoproliferation. Fewer than 10% of CVID patients have a known monogenic basis. Several chromosomal abnormalities (chromosome 18q-syndrome, monosomy 22, trisomy 8 and trisomy 21) are currently identified as causes of hypogammaglobulinaemia, and can manifest with recurrent infections and mimic CVID. METHODS: Review of clinical charts and laboratory results of paediatric patients followed in the outpatient clinic of PID with a diagnosis of genetic disease and humoral immunodeficiency. RESULTS: Three patients with different genetic diseases (19p13.3 deletion, a ring 18 chromosome and Kabuki syndrome), were identified. During follow-up, they developed signs and symptoms suggestive of humoral deficiency mimicking CVID, despite which immunoglobulin levels were quantified with considerable delay with respect to symptoms onset, and specific management was subsequently delayed. CONCLUSIONS: Patients with genetic abnormalities and recurrent infections should be evaluated for hypogammaglobulinaemia. An early diagnosis of humoral deficiency can allow treatment optimisation to prevent complications and sequelae.

Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome.

BACKGROUND: Kabuki syndrome (KS) is a complex multisystem developmental disorder associated with mutation of genes encoding histone-modifying proteins. In addition to craniofacial, intellectual, and cardiac defects, KS is also characterized by humoral immune deficiency and autoimmune disease, yet no detailed molecular characterization of the KS-associated immune phenotype has been reported. OBJECTIVE: We sought to characterize the humoral immune defects found in patients with KS with lysine methyltransferase 2D (KMT2D) mutations. METHODS: We comprehensively characterized B-cell function in a cohort (n = 13) of patients with KS (age, 4 months to 27 years). RESULTS: Three quarters (77%) of the cohort had a detectable heterozygous KMT2D mutation (50% nonsense, 20% splice site, and 30% missense mutations), and 70% of the reported mutations are novel. Among the patients with KMT2D mutations (KMT2D(Mut/+)), hypogammaglobulinemia was detected in all but 1 patient, with IgA deficiency affecting 90% of patients and a deficiency in at least 1 other isoform seen in 40% of patients. Numbers of total memory (CD27(+)) and class-switched memory B cells (IgM(-)) were significantly reduced in patients with KMT2D(Mut/+) mutations compared with numbers in control subjects (P < .001). Patients with KMT2D(Mut/+) mutations also had significantly reduced rates of somatic hypermutation in IgG (P = .003) but not IgA or IgM heavy chain sequences. Impaired terminal differentiation was noted in primary B cells from patients with KMT2D(Mut/+) mutations. Autoimmune pathology was observed in patients with missense mutations affecting the SET domain and its adjacent domains. CONCLUSIONS: In patients with KS, autosomal dominant KMT2D mutations are associated with dysregulation of terminal B-cell differentiation, leading to humoral immune deficiency and, in some cases, autoimmunity. All patients with KS should undergo serial clinical immune evaluations.

Immunologic assessment and KMT2D mutation detection in Kabuki syndrome.

Kabuki or Niikawa-Kuroki syndrome (KS) is a rare disorder with multiple malformations and recurrent infections, especially otitis media. This study aimed to investigate the genetic defects in Kabuki syndrome and determine if immune status is related to recurrent otitis media. Fourteen patients from 12 unrelated families were enrolled in the 9-year study period (2005-2013). All had Kabuki faces, cleft palate, developmental delay, mental retardation, and the short fifth finger. Recurrent otitis media (12/14) and hearing impairment (8/14) were also more common features. Immunologic analysis revealed lower memory CD19+ cells (11/13), lower memory CD4+ cells (8/13), undetectable anti-HBs antibodies (7/13), and antibody deficiency (7/13), including lower IgA (4), IgG (2), and IgG2 (1). Naïve emigrant lymphocytes, lymphocyte proliferation function, complement activity, and superoxide production in polymorphonuclear cells were all normal. All the patients had KMT2D mutations and 10 novel mutations of R1252X, R1757X,Y1998C, P2550R fs2604X, Q4013X, G5379X, E5425K, R5432X, R5432W, and R5500W. Resembling the phenotype of common variable immunodeficiency, KS patients with antibody deficiency, decreased memory cells, and poor vaccine response increased susceptibility to recurrent otitis media. Large-scale prospective studies are warranted to determine if regular immunoglobulin supplementation decreases the frequency of otitis media and severity of hearing impairment.

The diagnosis of autoimmune inner ear disease: evidence and critical pitfalls.

The purpose of this paper is to review the current diagnostic work-up for patients with suspected Autoimmune Inner Ear Disease (AIED). AIED is a rare disease accounting for less than 1% of all cases of hearing impairment or dizziness, characterized by a rapidly progressive, often fluctuating, bilateral SNHL over a period of weeks to months. While specific tests for autoimmunity to the inner ear would be valuable, at the time of writing, there are none that are both commercially available and proven to be useful. Thus far, most of the identified antigens lack a clear association with localized inner ear pathology and the diagnosis of AIED is based either on clinical criteria and/or on a positive response to steroids. For clinical practice, we recommend an antigen-non-specific test battery including blood test for autoimmune disorders and for conditions that resemble autoimmune disorders. Nevertheless, if financial resources are limited, a very restricted work-up study may have a similar efficiency.

Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study.

OBJECTIVE: Immune-mediated cochleovestibular disorders (IMCVDs) continue to present a management challenge to the otolaryngologist. Antirheumatic agents, commonly used for IMCVDs, are associated with variable efficacy and sometimes with serious side effects. The authors describe the preliminary result of their experience in patients with IMCVDs who have been treated with etanercept, a tumor necrosis factor alpha receptor blocker, recently approved by the United States Food and Drug Administration for the treatment of rheumatoid arthritis. STUDY DESIGN: Retrospective case series. SETTING: Tertiary care hospital. PATIENTS: Twelve patients suspected of having IMCVD who did not respond to conventional therapies or experienced side effects of the conventional therapies. INTERVENTION: Etanercept 25 mg by subcutaneous injection twice per week. MAIN OUTCOME MEASURES: The main outcome measurement was assessment of hearing change by air conduction pure tone audiograms and/or word discrimination. When present, vertigo, tinnitus, and aural fullness were assessed as well. RESULTS: Follow-up of more than 5 months was available for all patients (range, 5-12 months). Eleven (92%) of 12 patients had improvement or stabilization of hearing and tinnitus, seven (88%) of eight patients who had vertigo and eight (89%) of nine patients who had aural fullness had resolution or significant improvement of their symptoms. The benefit persisted until the last visit (5-12 months after etanercept was begun). The condition of one patient improved dramatically at first but deteriorated after 5 months. The patient's hearing was rescued and stabilized with the addition of leflunomide to etanercept. Similarly, three other patients required a second antirheumatic agent to stabilize their hearing. There were no significant side effects from the etanercept therapy. CONCLUSIONS: Our limited data suggest that etanercept therapy is safe and may be efficacious in carefully selected patients with IMCVDs, at least on a short-term basis. These preliminary efficacy and safety results appear encouraging enough to warrant further follow-up and studies for better determination of the potential clinical utility of etanercept for IMCVDs.

Thoracoabdominal aortic aneurysm in Cogan's syndrome.

Cogan's syndrome is an autoimmune disease of unknown etiology, clinically manifested as non-syphilitic interstitial keratitis and audiovestibular symptoms. Increasing evidence suggests that Cogan's may be a systemic vasculitis. In this report, we review the vascular manifestations of Cogan's syndrome and report two cases of thoracoabdominal aortic aneurysm in patients with this disorder.

Lipopolysaccharide-induced expression of nitric oxide synthase II in the guinea pig vestibular end organ.

The purpose of the investigation was to ascertain whether inoculation of bacterial lipopolysaccharide (LPS) into the vestibular organ of the guinea pig might induce formation of nitric oxide synthase (NOS) II. Forty-eight hours after the animals were injected with 1 mg transtympanic LPS, varying degrees of impaired caloric responses were observed with similar degeneration of vestibular hair cells. These effects could be blocked with N-nitro-L-arginine methylester, a competitive inhibitor of NOS. Findings suggested that NOS II, which was not normally detectable in the guinea pig vestibular organ but was present following inoculation of LPS, produced the nitric oxide as the toxic factor causing cell damage. If true, LPS may represent a reproducible method for studying the vestibular pathogenesis of inner ear disease.

[Bilateral vestibular loss as a post-infection complication of yersiniosis?]. / Bilateraler Vestibularisausfall als postinfektiöse Komplikation einer Yersiniose?

BACKGROUND: Yersinia infections other than plaque are caused by Yersinia pseudotuberculosis and Yersinia enterocolitica. Food and water contamination as well as animal-to-person and person-to-person contact are common pathways of transmission. Clinical manifestations include enteritis, enterocolitis, acute appendicitis, inflammation of the terminal ileum, and mesenteric adenitis. Y. enterocolitica may cause bacteremia with subsequent septicemia predominantly in patients with underlying illnesses such as diabetes mellitus or malignancy. More frequently enteritis is followed by immunological post-infectious syndromes such as arthritis and erythema nodosum. The present case report discusses bilateral vestibular loss possibly caused by an infection with Y. enterocolitica. PATIENTS: A 27-year-old caucasian woman initially presented with the otologic symptom of spinning vertigo accompanied by nausea and vomiting. RESULTS: Physical exam revealed spontaneous nystagmus to the left. Bithermal caloric responses were absent. Pure tone audiometry showed a bilateral symmetric high-frequency sensorineural hearing loss. Neurologic exams did not reveal involvement of the central vestibular system. Perilymphatic fistula on the left side was excluded by tympanoscopy. Serology for rheumatoid factors and HLA B27 was negative. Lead or mercury intoxication was also excluded. In her medical history the patient reported intermittent watery diarrhea and stress dependent arthralgia that had commenced during a stay in Argentina three years ago. Serology was positive, revealing elevated titers for Y. enterocolitica type 3 (1:200) and type 9 (1:400). DISCUSSION: Bilateral vestibular loss is rare. The main cause is aminoglycoside ototoxicity or meningitis. Yersina infections have not yet been described as inducing disease of the labyrinth. Present pathophysiologic knowledge of yersinia infections is described as follows: After peroral infection, gastrointestinal permeability is increased. Low-molecular-weight substances may enter the bloodstream and stimulate the formation of circulating immune complexes. These are held responsible for extraintestinal manifestations of yersinosis. Whether these circulating immune complexes and antibodies against Y. enterocolitica have an effect on the inner ear remains unclear. CONCLUSION: Because the coincidence of yersiniosis and a bilateral vestibular loss with no other identified cause, a postinfectious immune response is suggested as possible pathogenic mechanism.

Differential expression of transthyretin in papillary tumors of the endolymphatic sac and choroid plexus.

Aggressive papillary tumors of the temporal bone, occurring sporadically or as part of von Hippel-Lindau disease, have been shown to originate within the endolymphatic sac or duct. Also implicated as a potential precursor from which some of these tumors may arise is ectopic choroid plexus epithelium. To aid in the differentiation between papillary tumors of endolymphatic sac and duct origin and those arising from choroid plexus, an immunohistochemical study using stains for transthyretin (TTR), cytokeratins, S-100 protein, epithelial membrane antigen (EMA), and glial fibrillary acidic protein (GFAP) was carried out on archival specimens of normal and neoplastic endolymphatic sac and duct and choroid plexus epithelium. Transthyretin, a marker for choroid plexus epithelium, was found to show differential expression between choroid plexus papillomas and aggressive papillary tumors of the endolymphatic sac or duct. Therefore the use of TTR in concert with other immunohistochemical stains appear to aid in the differentiation between intracranial and intratemporal papillary tumors arising from choroid plexus and endolymphatic sac or duct epithelium.

Methotrexate management of immune-mediated cochleovestibular disorders.

Immune-mediated cochleovestibular disorders continue to present a management challenge to the otolaryngologist. The traditional treatment of these disorders, corticosteroids and/or cyclophosphamide (Cytoxan), has been associated with serious and occasionally life-threatening complications. In this study we report our experience in treating 25 patients with immune-mediated cochleovestibular disorders with methotrexate, a less toxic immunosuppressive agent that has been used extensively in patients with rheumatoid arthritis. Mean duration of treatment was 12.9 months, and adverse reactions were acceptable and reversible. Hearing improved in 69.6% of patients, and vestibular symptoms subsided or improved in 80% of patients. The results of this study suggest that methotrexate treatment is effective in a substantial number of patients with immune-mediated cochleovestibular disorders and has acceptable adverse reactions. A prospective, randomized study is needed to compare the efficacy of methotrexate with that of other immunosuppressive agents.

[A case of myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA)-related glomerulonephritis associated with Cogan's syndrome].

We report here a case of Cogan's syndrome associated with systemic vasculitis as well as myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA)-related glomerulonephritis. A 71-year-old woman with the diagnosis of aortitis syndrome and pulmonary fibrosis for 7 years, complained of vertigo and hearing impairment. A diagnosis of serous otitis media was made. Although steroid therapy was effective, the symptoms relapsed several times. Seven months after the first manifestation of aural symptoms, she developed painful red eyes bilaterally and proteinuria. On admission, perinuclear ANCA without cytoplasmic ANCA was detected by indirect immunofluorescence assay and MOP-ANCA was detected by enzyme linked immunosorbent assay using the 363 ELISA Unit. Renal biopsy showed necrotizing crescentic glomerulonephritis without immune deposits. A diagnosis of atypical Cogan's syndrome with systemic vasculitis and pulmonary fibrosis was made from the clinical and histological findings. As nephrotic syndrome progressed after admission, she was started on high-dose corticosteroid administration. Urinary protein and other symptoms, except for hearing acuity, improved in parallel with a decrease in the MPO-ANCA titer to normal values. While tapering the dose of corticosteroid, the MPO-ANCA titer increased again and dyspnea occurred. Although pulse methylpredonisolone therapy was performed, the patient died of respiratory failure complicated with sepsis. Postmortem lung biopsy showed pulmonary fibrosis and massive alveolar hemorrhage. The findings of this case study suggest that MPO-ANCA may be closely related to the pathogenesis of Cogan's syndrome.